Clinical and translational medicine · 2026
TMEM92 shields DDX3X from TTC3-mediated degradation to confer chemoresistance in triple-negative breast cancer.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Shen Hao, Jia Xiaochao, Li Xu, Li Zhi, Zhang Zhihua, Zhao Yang, Shen Lei, Bu Xiaoqiu, Ma Qiang, Liang Chunli, Lin Xiaoti, Ma Lin-Xiaoxi, Qin Chuan
Аннотация
BACKGROUND: Triple-negative breast cancer (TNBC) remains a major clinical challenge because of its aggressive characteristics, limited targeted treatment options, and frequent chemoresistance. However, the molecular mechanisms governing protein stability that drive TNBC progression and therapeutic resistance remain incompletely understood.
METHODS: TMEM92 expression and clinical relevance were evaluated using public datasets, patient specimens, and TNBC cell models. Loss-of-function, rescue, xenograft, protein interaction, and ubiquitination assays were performed to determine the biological function and molecular mechanism of TMEM92 in TNBC progression and cisplatin response.
RESULTS: TMEM92 was prominently expressed in TNBC and correlated with poor prognosis. Functionally, depletion of TMEM92 suppressed TNBC cell proliferation, migration, invasion, and survival while promoting apoptosis in vitro and in vivo. Mechanistically, TMEM92 directly associated with DEAD-box helicase 3 X-linked (DDX3X) and protected it from degradation by the E3 ubiquitin ligase tetratricopeptide repeat domain 3 (TTC3). TMEM92 competitively prevented TTC3 binding to DDX3X, thereby inhibiting TTC3-mediated K48-linked ubiquitination and subsequent proteasomal degradation of DDX3X. Re-expression of DDX3X rescued the anti-tumor effects induced by TMEM92 knockdown. Therapeutically, TMEM92 targeting sensitized TNBC cells and xenograft tumors to cisplatin. TMEM92 knockout reduced the cisplatin IC50 by 44.0% in MDA-MB-231 cells and 42.9% in BT-549 cells, and TMEM92 depletion enhanced cisplatin-induced tumor growth inhibition by approximately 70.6% compared with cisplatin alone.
CONCLUSIONS: This study identifies a novel TMEM92DDX3XTTC3 axis that regulates DDX3X protein stability and drives TNBC progression and chemoresistance, revealing a potential prognostic and therapeutic vulnerability in TNBC.
METHODS: TMEM92 expression and clinical relevance were evaluated using public datasets, patient specimens, and TNBC cell models. Loss-of-function, rescue, xenograft, protein interaction, and ubiquitination assays were performed to determine the biological function and molecular mechanism of TMEM92 in TNBC progression and cisplatin response.
RESULTS: TMEM92 was prominently expressed in TNBC and correlated with poor prognosis. Functionally, depletion of TMEM92 suppressed TNBC cell proliferation, migration, invasion, and survival while promoting apoptosis in vitro and in vivo. Mechanistically, TMEM92 directly associated with DEAD-box helicase 3 X-linked (DDX3X) and protected it from degradation by the E3 ubiquitin ligase tetratricopeptide repeat domain 3 (TTC3). TMEM92 competitively prevented TTC3 binding to DDX3X, thereby inhibiting TTC3-mediated K48-linked ubiquitination and subsequent proteasomal degradation of DDX3X. Re-expression of DDX3X rescued the anti-tumor effects induced by TMEM92 knockdown. Therapeutically, TMEM92 targeting sensitized TNBC cells and xenograft tumors to cisplatin. TMEM92 knockout reduced the cisplatin IC50 by 44.0% in MDA-MB-231 cells and 42.9% in BT-549 cells, and TMEM92 depletion enhanced cisplatin-induced tumor growth inhibition by approximately 70.6% compared with cisplatin alone.
CONCLUSIONS: This study identifies a novel TMEM92DDX3XTTC3 axis that regulates DDX3X protein stability and drives TNBC progression and chemoresistance, revealing a potential prognostic and therapeutic vulnerability in TNBC.